Radioiodine-refractory Thyroid Cancer Research Articles

Metabolomic screening of radioiodine refractory thyroid cancer patients and the underlying chemical mechanism of iodine resistance

Radioiodine refractory (RAIR) patients do not benefit from iodine-131 therapy. Thus, timely identification of RAIR patients is critical for avoiding ineffective radioactive iodine therapy. In addition, determining the causes of iodine resistance will facilitate the development of novel treatment strategies. This study was comprised of 20 RAIR and 14 non-radioiodine refractory (non-RAIR) thyroid cancer patients. Liquid chromatography-mass spectrometry was used to identify differences in the serum metabolites of RAIR and non-RAIR patients. In addition, chemical assays were performed to determine the effects of the differential metabolites on iodine uptake. Metabolic pathway enrichment analysis of the differential metabolites revealed significant differences in the phenylalanine and tyrosine metabolic pathways. Notably, quinate and shikimic acid, metabolites of the tyrosine pathway, were significantly increased in the RAIR group. In contrast, the phenylalanine pathway metabolites, hippuric acid and 2-phenylacetamide, were markedly decreased in the RAIR group. Thyroid peroxidase plays an important role in catalyzing the iodination of tyrosine residues, while the ionic state of iodine promotes the iodination reaction. Quinate, shikimic acid, hippuric acid, and 2-phenylacetamide were found to be involved in the iodination of tyrosine, which is a key step in thyroid hormone synthesis. Specifically, quinate and shikimic acid were found to inhibit iodination, while hippuric acid and 2-phenylacetamide promoted iodination. Abnormalities in phenylalanine and tyrosine metabolic pathways are closely associated with iodine resistance. Tyrosine is required for thyroid hormone synthesis and could be a potential cause of iodine resistance.

“Watch and wait” approach in the treatment of advanced radioiodine refractory differentiated thyroid cancer: a study of barriers and drivers of use

Introduction. The multikinase inhibitors have demonstrated high clinical efficacy in treatment of the radioiodine refractory differentiated thyroid cancer. At the same time, the inclusion criteria in the studies has reflected a minimum set of characteristics important for beginning of use of these drugs and an approach that takes into account the tumor progression rate (the volume doubling time) in the absence of clinical manifestations of the disease that have made it possible to individualize the start of therapy. Aim. To describe and evaluate the barriers and drivers of use the “watch and wait” approach by Russian oncologists in treatment of the radioiodine refractory thyroid cancer. Materials and methods. We conducted 35 structured interviews with oncologists observing patients after radioiodine therapy in order to evaluate the “watch and wait” approach. unfortunately, data on use and prevalence of this approach in Russia are limited. The present study involved the use of deductive content analysis as well as analysis of implementation model of clinical guidelines and included investigation of issue of implementation of the “watch and wait” approach to current practice of therapy for radioiodine refractory differentiated thyroid cancer. One of the main tasks was to determine the influence of external factors on the treatment of this category of patients. Conclusion. Barriers and drivers of using “watch and wait” approach in the treatment of differentiated radioiodine refractory thyroid cancer are identified at several levels. for wide use of this approach, it is necessary to involve oncologists taking into account their attitude regarding changes in routine practices, patient expectations and to obtain additional data regarding its long-term effectiveness.

Clinico-pathological factors associated with radioiodine refractory differentiated thyroid carcinoma status.

Risk factors for developing radioiodine refractory thyroid cancer (RAIR-TC) have rarely been analyzed. The purpose of the present study was to find clinical and pathological features associated with the occurrence of RAIR-disease in differentiated thyroid cancers (DTC) and to establish an effective predictive risk score. All cases of RAIR-DTC treated in our center from 1990 to 2020 were retrospectively reviewed. Each case was matched randomly with at least four RAI-avid DTC control patients based on histological and clinical criteria. Conditional logistic regression was used to examine the association between RAIR-disease and variables with univariate and multivariate analyses. A risk score was then developed from the multivariate conditional logistic regression model to predict the risk of refractory disease occurrence. The optimal cut-off value for predicting the occurrence of RAIR-TC was assessed by receiver operating characteristic (ROC) curves and Youden's statistic. We analyzed 159 RAIR-TC cases for a total of 759 controls and found 7 independent risk factors for predicting RAIR-TC occurrence: age at diagnosis ≥ 55, vascular invasion, synchronous cervical, pulmonary and bone metastases at initial work-up, cervical and pulmonary recurrence during follow-up. The predictive score of RAIR-disease showed a high discrimination power with a cut-off value of 8.9 out of 10 providing 86% sensitivity and 92% specificity with an area under the curve (AUC) of 0.95. Predicting the occurrence of RAIR-disease in DTC patients may allow clinicians to focus on systemic redifferentiating strategies and/or local treatments for metastatic lesions rather than pursuing with ineffective RAI-therapies.

Prognostic Roles of Inflammatory Biomarkers in Radioiodine-Refractory Thyroid Cancer Treated with Lenvatinib.

Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), serve as valuable prognostic indicators in various cancers. This multicenter, retrospective cohort study assessed the treatment outcomes of lenvatinib in 71 patients with radioactive iodine (RAI)-refractory thyroid cancer, considering the baseline inflammatory biomarkers. This study retrospectively included patients from five tertiary hospitals in Korea whose complete blood counts were available before lenvatinib treatment. Progression-free survival (PFS) and overall survival (OS) were evaluated based on the median value of inflammatory biomarkers. No significant differences in baseline characteristics were observed among patients grouped according to the inflammatory biomarkers, except for older patients with a higher-than-median NLR (≥2) compared to their counterparts with a lower NLR (P= 0.01). Patients with a higher-than-median NLR had significantly shorter PFS (P=0.02) and OS (P=0.017) than those with a lower NLR. In multivariate analysis, a higher-than-median NLR was significantly associated with poor OS (hazard ratio, 3.0; 95% confidence interval, 1.24 to 7.29; P=0.015). However, neither the LMR nor the PLR was associated with PFS. A higher-than-median LMR (≥3.9) was significantly associated with prolonged OS compared to a lower LMR (P=0.036). In contrast, a higher-than-median PLR (≥142.1) was associated with shorter OS compared to a lower PLR (P=0.039). Baseline inflammatory biomarkers can serve as predictive indicators of PFS and OS in patients with RAI-refractory thyroid cancer treated with lenvatinib.

Tyrosine kinase inhibitors for radioiodine refractory differentiated thyroid cancer: A systematic review and meta-analysis.

The poor overall prognosis of radioiodine refractory thyroid cancer is an inevitable challenge in managing this disease. A series of trials have demonstrated the antitumor activity of tyrosine kinase inhibitors (TKIs)in radioiodine refractory differentiated thyroid cancer (RAIR-DTC).However, the available evidence cannot determine the optimal choice of TKI in RAIR-DTC. This study searched PubMed, EMBASE, Cochrane databases, and the ClinicalTrials website. The Cochrane bias risk tool was used to assess the risk of bias, and to evaluate randomized clinical trials (RCT)of RAIR-DTCpatients treated with the TKI system. Outcomes, including progression-free survival (PFS),overall survival (OS),and adverse events (AEs)were reported. Seven studies involving 1310 patients with RAIR-DTCwas conducted to compare the PFS and OS of various TKImonotherapies with placebo. The results showed that all TKI monotherapies had a statistically significant benefit in terms of PFS compared with placebo, with lenvatinib demonstrating the greatest benefit (hazard ratio [HR]0.19, 95% credible interval [CrI] 0.14-0.25). In terms of OS, only apatinib (HR 0.42, 95% CrI 0.18-0.97) and anlotinib (HR0.36, 95% CrI 0.18-0.73) showed statistically significant benefits compared with placebo. TKIs also had a higher incidence of AEs of grade 3 or higher compared with placebo. The findings suggest that lenvatinib may be the preferred TKI for the treatment of RAIR-DTC,although its high incidence of AEs should be considered. The results also indicate that TKI treatment may be similarly effective in RAIR-DTCpatients with BRAF or RAS mutations and in those with papillary or follicular subtypes of the disease, regardless of prior TKI treatment. The results of this meta-analysis suggest that targeted therapy with TKIs may be beneficial for patients with radioiodine-refractory advanced or metastatic differentiated thyroid cancer. Among the TKIs analyzed, lenvatinib appeared to be the most effective at improving PFS, although it also had the highest incidence of AEs. Further research through direct randomized controlled trials is needed to determine the optimal choice of TKI for treating patients with RAIR-DTC.This study is beneficial for formulating patients' treatment plans and guides clinicians' decision-making.

Chapter 8: Management of Radioiodine Refractory Thyroid Cancer

ABSTRACT A small subset of patients with differentiated thyroid cancers (DTCs), over the course of their natural disease progression, undergo dedifferentiation which leads to altered tumor biology and an inability to concentrate and respond to radioactive iodine (RAI), despite being able to functionally produce and release thyroglobulin. They broadly consist of two groups – (a) thyroglobulin-elevated negative iodine scintigraphy and (b) radioiodine refractory DTC. This review deals with their definitions, presentation, and overall management principles, highlighting the key points of their treatment philosophy. Whole-body 18F positron emission tomography-computed tomography is the investigation of choice since majority of these become fludeoxyglucose avid once they lose their iodine avidity. Asymptomatic patients with low disease burden may be observed. Surgical ablation, for symptomatic patients with accessible disease is the prime treatment modality. For those deemed inoperable with high tumor burden and increasing symptomatology are best treated with multikinase inhibitors. External beam Radiation may be a choice for painful bony metastasis, while those refractory to multikinase inhibitors may be offered newer forms of localized therapy such as radiofrequency ablation, newer isotope therapy, and transarterial chemoembolization.

Clinical impact of proteinuria on renal function and treatment outcomes in patients with radioiodine-refractory thyroid cancer treated with lenvatinib.

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74-39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31-46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22-13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0-2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

Factors associated with lenvatinib adherence in thyroid cancer and hepatocellular carcinoma.

Lenvatinib is an oral anticancer medication used to treat radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma. The purpose of this study is to evaluate lenvatinib adherence by patients and to identify factors associated with decreased lenvatinib adherence. Among 153 patients who started treatment with lenvatinib for unresectable thyroid cancer or unresectable hepatocellular carcinoma between May 1, 2015 and August 31 2021 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 102 were eligible for this study (55 thyroid cancer, 47 hepatocellular carcinoma). The lenvatinib adherence rate in a treatment cycle was defined as the number of times a patient took lenvatinib in a 28-day cycle divided by the prescribed 28 doses. The rate was determined by pill counting and self-reporting at the pharmaceutical outpatient clinic. Reasons for non-adherence were established by interview and analyzed. The median adherence rate of lenvatinib in the first cycle was 90.1% (n = 55) in thyroid cancer and 94.9% (n = 47) in hepatocellular carcinoma. In thyroid cancer, there were 255 incidents of lenvatinib non-adherence. Non-adherence was mainly associated with bleeding events (18.6%), followed by hand-foot skin reactions (10.6%). In hepatocellular carcinoma, there were 97 incidents of non-adherence. Hypertension accounted for 20.6%, followed by hoarseness (18.6%) and diarrhea (17.5%). The adherence rate for lenvatinib in Japanese patients with thyroid and hepatocellular carcinoma in real-world clinical practice was more than 90% in this study. Hypertension was a major reason for non-adherence, followed by hand-foot skin reactions and diarrhea.

Coronary Artery and Peripheral Vascular Disease in a Patient with Poorly Differentiated Thyroid Cancer Treated with the Tyrosine Kinase Inhibitor Lenvatinib

A subset of patients with differentiated thyroid carcinoma develop radioiodine refractory (RAIR) incurable disease, which typically has a poor prognosis. The multitargeted tyrosine kinase inhibitor lenvatinib has demonstrated significant improvements in progression-free survival in RAIR thyroid cancers compared to placebos. However, in the phase III SELECT trial of the drug in thyroid cancer, 5.4% of patients on lenvatinib experienced arterial thromboembolic events, with 2.7% experiencing severe grade ≥3 toxicities associated with arterial vascular events. This case study reports a patient with metastatic poorly differentiated follicular thyroid cancer who developed significant obstructive coronary artery disease following initiation of lenvatinib treatment, despite no predisposing cardiovascular risk factors apart from a remote smoking history. The possibility of developing coronary or peripheral artery disease should be considered in patients who are on targeted therapies, such as lenvatinib, even in the absence of traditional cardiovascular risk factors. In addition, baseline cardiac risk assessment and early treatment should be pursued to minimize interruptions to potentially lifesaving cancer therapy.

SAT543 A Case of Non-iodine-Avid Papillary Thyroid Cancer With a Rare Distant Metastasis to the Pancreas

Abstract Disclosure: A.H. Alcain: None. M.C. Isidro: None. Papillary Thyroid Carcinoma is the most common type of differentiated thyroid cancer. Distant metastasis is rare occurring only in 5% of patients and typically involves the lungs and bones. Metastasis to the pancreas is extremely rare with few cases reported over the years. We present a case of a 65-year-old female, who presented with sudden onset of abdominal pain. A review of the patient’s medical history revealed a history of a non-iodine avid Papillary Thyroid Carcinoma in 2015. The patient underwent Radioactive Iodine (RAI) ablation therapy twice due to elevated Thyroglobulin (Tg) levels. Despite RAI, Tg levels were still elevated with no recurrence nor metastasis noted on scan. Chemotherapy was offered but the patient opted for Tomotherapy. The patient completed Tomotherapy in 2017 but afterward was lost to follow-up. A CT scan of the abdomen showed findings of a pancreatic tail and body mass (10 x 7 cm) with an invasion of the mid-descending colon with pulmonary nodules which are possibly metastatic. The patient underwent an endoscopic ultrasound-guided biopsy, and pathology showed findings of a pancreatic papillary neoplasm (CK and beta-catenin positive, synaptophysin negative). Chemotherapy was given (FOLFOX) and a PET scan was requested to monitor the response to treatment. However, PET-scan showed FDG-avid (SUV 32.1) mass in the pancreatic tail (7.2 x 7.8 x 13.3 cm), FDG-avid (SUV 17.61) nodules in the lungs, and an ill-defined heterogeneous mass in the left surgical site (2.2 x 2.6 x 5.3 cm). Given that patient had a thyroidectomy in 2015, recurrence was considered. The possibility of probable metastasis to the pancreas was entertained hence re-biopsy was done. Serum Tg levels were elevated (4,115 ng/ml NV: 1.59-50.0) and negative for Anti-Tg. Biopsy showed high-grade neoplasm with papillary features. IHC staining showed positive for CK7, Tg, and TTF-1, and negative for CK20 which was consistent with metastatic papillary thyroid carcinoma. The patient was given Lenvatinib and is at present tolerating the treatment well with evidence of decreasing Tg levels suggesting a response to treatment. This is a case of a rare site of distant metastasis of a non-iodine avid papillary thyroid carcinoma. Targeted therapy such as Tyrosine kinase inhibitors can improve the survival rate of patients with Radioiodine Refractory Thyroid cancers. Metastasis should be considered especially in patients with a history of prior malignancy. Presentation Date: Saturday, June 17, 2023

Impact of local treatments in progressive, advanced, radioiodine-refractory thyroid cancer

Impact of local treatments in progressive, advanced, radioiodine-refractory thyroid cancer

Real-World Use of Systemic Therapies for the Treatment of Advanced Thyroid Cancers

ObjectiveIn the last decade, new systemic treatment options have been made available for patients with advanced thyroid cancer. However, little is known about the real-world utilization of these systemic therapies. MethodsWe used Optum’s de-identified Clinformatics® Data Mart Database to characterize trends in the use of 15 systemic therapies that are available for the treatment of advanced thyroid cancer between 2013 and 2021. Joinpoint regression was used to calculate annual percentage changes in the use of systemic therapy by patients’ race/ethnicity. The sequence of therapies was determined by the date of prescription claims. ResultsBetween 2013 and 2021, the annual number of patients treated for advanced thyroid cancer with systemic therapy increased from 45 patients in 2013 to 114 patients in 2021 (N of total cohort = 885). Most patients were female (54.7%) and non-Hispanic White (62.1%). Between 2013 and 2021, there was a significant decrease in the proportion of non-Hispanic White patients treated for advanced thyroid cancer with systemic therapy (annual percentage change −3.9%, 95% confidence intervals, −6.0% to −1.8%). Since its approval by the US Food and Drug Administration (FDA) in 2015, lenvatinib remains the most frequently prescribed first-line therapy for the treatment of radioiodine-refractory thyroid cancer (48.8% of patients between 2017 and 2021). Between 2017 and 2021, most patients (79.7%) were initiated on 1 of the 10 FDA-approved agents and 81.7% received only a first-line therapy. ConclusionsBetween 2013 and 2021, the use of systemic treatment options for advanced thyroid cancer increased significantly, largely driven by the prescription of lenvatinib following its approval by the FDA in 2015, with an increasing trend for use in non-White patients.

NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer

PurposePathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC).MethodsA total of 184 TC patients with testing for NTRK gene fusions were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan–Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy.Results8/184 (4%) patients harbored NTRK gene fusions. Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 (n = 4) and NTRK3 (n = 2) gene fusions were treated with larotrectinib. Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy. All patients had morphologically progressive disease before treatment initiation. Objective response rate was 83%, including two complete remissions. Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0–57.4) and median OS was not reached (NR) (95% CI, NR). Adverse events were of grade 1–3.ConclusionThe prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile.

Significance of thyroglobulin autoantibodies in patients with thyroid cancer treated with lenvatinib

Abstract Context Serum thyroglobulin (Tg) is a highly sensitive and specific tumor marker, employed in post-operative management of patients with differentiated thyroid carcinomas (DTC). Tumor shrinkage of radioiodine-refractory thyroid cancer (RAIR-DTC) treated with multi-target kinase inhibitors as Lenvatinib, expressed according to RECIST, is also associated with a drastic reduction of Tg levels. However, interference caused by circulating Thyroglobulin Autoantibodies (TgAb) represents the main limitation in the clinical use of Tg. Objective To evaluate if in RAIR-DTC TgAb could be considered a surrogate marker of Tg, in monitoring response to treatment with lenvatinib Design We retrospectively evaluated patients who had started lenvatinib, and correlated serum Tg and TgAb with the radiological response across visits. Setting University of Pisa, Italy Patients We selected 9/97 RAIR-DTC patients with detectable TgAb Intervention none Main Outcome Measure(s) none Results Tg values correlated neither with TgAb title nor with radiological response across visits. Greater decreases in TgAb titer correlated with favorable radiological response to lenvatinib after 1 month (Spearman’s correlation = 0.74, p = 0.021) and 6 months (correlation = 0.61, p = 0.079). According to RECIST, patients with partial response showed a ∼10-fold greater decrease in TgAb compared to those with stable disease at 1 month (median TgAb decrease: −142 vs −14 IU/mL, p = 0.01) and those with progressive disease at 6 months (median TgAb decrease: −264 vs−24 IU/mL, p = 0.04). Conclusion TgAb evaluation may represent a reliable surrogate marker for Tg trend in evaluating response of RAIR-DTC to treatment with Lenvatinib. A multicentric study would be useful to confirm our results.

Greetings From the Editor of Clinical Thyroidology

Clinical ThyroidologyVol. 35, No. 5 Greetings from the EditorFree AccessGreetings From the Editor of Clinical ThyroidologyPublished Online:12 May 2023https://doi.org/10.1089/ct.2023;35.176-177AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Welcome to another issue of Clinical Thyroidology. The month's issue begins with a review by Dr. Elizabeth McAninch on the intersection between thyroid and renal function. Dr. Kenneth Burman summarizes a recent literature review on the topic of levothyroxine absorption tests in patients with hypothyroidism. Drs. Erivelto Volpi and Leonardo Volpi examine a study comparing the cost effectiveness between total thyroidectomy and radioactive iodine therapy in patients who relapse after a course of anti-thyroid drugs. Drs. Trisha Cubb and Natalia Genere review a study on the risk of hyperglycemia associated with teprotumumab use in patients with thyroid eye disease.On the topic of thyroid nodules and thyroid cancer, Dr. Jie Liu discusses a study examining variation in the extent of thyroid surgery performed between types of geographical settings in the United States. Dr. Giorgio Grani examines a study that analyzed the association of delayed thyroid surgery and oncologic outcomes in patients with papillary thyroid cancers.There are also reviews of several studies in this issue related to follicular thyroid cancers. Dr. Sara Ahmadi discusses a study on the genomics of follicular thyroid lesions, while Dr. Theodora Pappa reviews the prognosis of patients with large encapsulated follicular cell–derived carcinomas without vascular invasion. Drs. Yasuhiro Ito and Takashi Akamizu look at a study that examines the TERT promoter mutation in patients with follicular thyroid cancers.The issue also includes a review by Dr. Giuseppe Barbesino on a phase 2 study of MAPK inhibitory agents in radioiodine-refractory thyroid cancers. Finally, Drs. Shejil Kumar, Matti Gild, and Venessa Tsang summarize a study of neoadjuvant therapy that might be lend hope to some patients with BRAF-mutated anaplastic thyroid cancers.We remain active on our various social media channels, and I invite our readers to further engage with us there. In these channels, we recap the featured highlights from each month's issue and discuss other topics related to the latest clinical thyroid literature. All are welcome to join us at:Twitter:https://twitter.com/clinicalthyroid(@clinicalthyroid)Facebook:https://www.facebook.com/ThyroidAssociationLinkedIn:https://www.linkedin.com/company/american-thyroid-associationYoutube:https://www.youtube.com/user/thyroidorgI also thank the editorial board of Clinical Thyroidology for the Public [CTFP] (https://www.thyroid.org/patient-thyroid-information/ct-for-patients), as led by Dr. Alan Farwell, for their work in providing short summaries of our Clinical Thyroidology articles each month. These quicker reads are helpful to patients and to the general public who are interested in learning more about recently published studies in the clinical thyroid literature.We will continue to provide reviews, commentaries, editorials, and perspectives of the most relevant clinical thyroid studies from the published literature. Guidelines for submitting Letters to the Editor and select Guest Editorials that cover timely and innovative aspects of clinical thyroid disease management may be found at https://home.liebertpub.com/publications/clinical-thyroidologyand174/623/for-authors.Thank you again for your interest in Clinical Thyroidology. Please feel free to send me any questions or comments at clinicalthyroidology@thyroid.org.Warmest regards,Angela M. Leung, MD, MScEditor-in-Chief, Clinical ThyroidologyFiguresReferencesRelatedDetails Volume 35Issue 5May 2023 Information© Copyright 2023, Mary Ann Liebert, Inc.To cite this article:Greetings From the Editor of Clinical Thyroidology.Clinical Thyroidology.May 2023.176-177.http://doi.org/10.1089/ct.2023;35.176-177Published in Volume: 35 Issue 5: May 12, 2023PDF download

Radio-iodine refractory thyroid cancer patients: a tailored follow-up based on clinicopathological features

ObjectiveTo report the experience of a single center for the selection of radioiodine-refractory (RAIR) thyroid cancer patients (RAIR-TC) who needed tyrosine kinase inhibitor (TKIs) treatment.Patients and methodsWe evaluated all features of 279 RAIR-TC patients both at the time of diagnosis and at the RAIR diagnosis.ResultsNinety-nine patients received indication to TKIs (Group A), while 180 remained under active surveillance (Group B). Group A had greater tumor size, more aggressive histotype, more frequent macroscopic extrathyroidal extension, distant metastases, advanced AJCC stage, and higher ATA risk of recurrence. After RAIR diagnosis, 93.9% of Group A had progression of disease (PD) after which TKIs’ therapy was started. The remaining 6.1% of patients had a so severe disease at the time of RAIR diagnosis that TKIs’ therapy was immediately started. Among Group B, 42.7% had up to 5 PD, but the majority underwent local treatments. The mean time from RAIR diagnosis to the first PD was shorter in Group A, and the evidence of PD within 25 months from RAIR diagnosis was associated with the decision to start TKIs.ConclusionsAccording to our results, a more tailored follow-up should be applied to RAIR-TC patients. A too strict monitoring and too many imaging evaluations might be avoided in those with less-aggressive features and low rate of progression. Conversely, RAIR-TC with an advanced stage at diagnosis and a first PD occurring within 25 months from RAIR diagnosis would require a more stringent follow-up to avoid a late start of TKIs.

Neutrophil-to-lymphocyte ratio as an independent factor for worse prognosis in radioiodine refractory thyroid cancer patients.

This study aimed to evaluate neutrophil to lymphocyte ratio (NLR) as a laboratory biomarker in radioactive iodine-refractory (RAIR) locally advanced and/or metastatic differentiated thyroid cancer (DTC) and determine its correlation with overall survival (OS). We retrospectively included 172 patients with locally advanced and/or metastatic RAIR DTC admitted between 1993 and 2021 at INCA. Age at diagnosis, histology, presence of distant metastasis (DM), DM site, neutrophil-to- lymphocyte ratio (NLR), imaging studies such as PET/CT results, progression free survival (PFS) and overall survival (OS) data were analyzed. NLR was calculated at the time of locally advanced and/or metastatic disease diagnosis and the cutoff value was 3. Survival curves were established using the Kaplan-Meier method. The confidence interval is 95%, and a p-value of less than 0.05 was considered statistically significant RESULTS: Out of 172 patients, 106 were locally advanced, and 150 presented DM at some point during follow-up. Regarding NLR data, 35 had NLR over 3 and 137 had NLR under 3. Higher NLR at was associated with shorter OS (6 vs. 10; p = 0.05) and with highest SUV on FDG PET-CT (15.9 vs. 7.7, p = 0.013). We found no association between higher NLR and age at diagnosis, DM or final status. NLR higher than 3 at the time of locally advanced and/or metastatic disease diagnosis is an independent fator for shorter OS in RAIR DTC patients. Noteworthy higher NLR was also associated with highest SUV on FDG PET-CT in this population.

The expression of HDAC9 and P300 in papillary thyroid carcinoma cell line.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and accounts for 85-90% of all thyroid cancers. Metastatic differentiated thyroid cancer, radioiodine-refractory thyroid cancer, and anaplastic thyroid cancer still lack effective therapeutic options. Here, we aimed to assess HDAC9 and P300 expression in the papillary thyroid carcinoma cell line and compare them with normal thyroid cells. Nthy-ori-3-1, a normal thyroid cell line, and BCPAP, a PTC cell line, were cultured for 24 and 48h and immunofluorescence staining was used to determine the levels of HDAC9 and P300 protein expression. HDAC9 paracrine release was assessed using an ELISA assay. HDAC9 protein expression was higher in both cell groups at the 48th hour than at the 24th hour; however, P300 protein expression was lower in BCPAP cells at the 48th hour than at the 24th hour. In comparison to Nthy-ori-3-1, BCPAP expressed more HDAC9 and P300 proteins. HDAC9 secretion slightly increased in Nthy-ori-3-1 cells from 24 to 48h. Furthermore, HDAC9 secretion in BCPAP cells dramatically decreased from 24 to 48h. Our findings revealed that the expression of HDAC9 and P300 was higher in the PTC cell line than in normal thyroid cells. This indicates that the acetylation mechanism in thyroid cancer cells is not the same as it is in healthy cells. Epigenetic studies may reveal the mechanisms underlying PTC with further analysis.

Potential Role of PSMA-Targeted PET in Thyroid Malignant Disease: A Systematic Review.

Recently, several studies introduced the potential use of positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals in radioiodine-refractory thyroid cancer (TC). The authors accomplished a comprehensive literature search of original articles concerning the performance of PSMA-targeted PET/CT in TC patients. Original papers exploring this molecular imaging examination in radioiodine-refractory TC patients undergoing restaging of their disease were included. A total of 6 documents concerning the diagnostic performance of PSMA-targeted PET/CT in TC (49 patients) were included in this systematic review. The included articles reported heterogeneous values of PSMA-targeted PET/CT detection rates in TC, ranging from 25% to 100% and overall inferior to [18F]-fluorodeoxyglucose PET/CT when the two molecular imaging examinations were compared. Two studies reported the administration of [177Lu]PSMA-radioligands with theragnostic purpose in three patients. The available literature data in this setting are limited and heterogeneous. The employment of PET with PSMA-targeting radiopharmaceuticals in this setting did not affect patient management. Nevertheless, prospective multicentric studies are needed to properly assess its potential role in TC patients.

MAPK Pathway Inhibitors in Thyroid Cancer: Preclinical and Clinical Data.

Thyroid cancer is the most common endocrine cancer, with a good prognosis in most cases. However, some cancers of follicular origin are metastatic or recurrent and eventually become radioiodine refractory thyroid cancers (RAIR-TC). These more aggressive cancers are a clinical concern for which the therapeutic arsenal remains limited. Molecular biology of these tumors has highlighted a hyper-activation of the Mitogen-Activated Protein Kinases (MAPK) pathway (RAS-RAF-MEK-ERK), mostly secondary to the BRAFV600E hotspot mutation occurring in about 60% of papillary cancers and 45% of anaplastic cancers. Therapies targeting the different protagonists of this signaling pathway have been tested in preclinical and clinical models: first and second generation RAF inhibitors and MEK inhibitors. In clinical practice, dual therapies with a BRAF inhibitor and a MEK inhibitor are being recommended in anaplastic cancers with the BRAFV600E mutation. Concerning RAIR-TC, these inhibitors can be used as anti-proliferative drugs, but their efficacy is inconsistent due to primary or secondary resistance. A specific therapeutic approach in thyroid cancers consists of performing a short-term treatment with these MAPK pathway inhibitors to evaluate their capacity to redifferentiate a refractory tumor, with the aim of retreating the patients by radioactive iodine therapy in case of re-expression of the sodium-iodide symporter (NIS). In this work, we report data from recent preclinical and clinical studies on the efficacy of MAPK pathway inhibitors and their resistance mechanisms. We will also report the different preclinical and clinical studies that have investigated the redifferentiation with these therapies.